tbuckley/cabot-search huggingface dataset:
DNA-methylation signature accurately differentiates pancreatic cancer from chronic pancreatitis in tissue and plasma
Authors: Yenan Wu, Isabelle Seufert, Fawaz N Al-Shaheri, Roman Kurilov, Andrea S Bauer, Mehdi Manoochehri, Evgeny A Moskalev, Benedikt Brors, Christin Tjaden, Nathalia A Giese, Thilo Hackert, Markus W Büchler, Jörg D Hoheisel
Journal: Gut (2023)

Objective Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Differentiation from chronic pancreatitis (CP) is currently inaccurate in about one-third of cases. Misdiagnoses in both directions, however, have severe consequences for patients. We set out to identify molecular markers for a clear distinction between PDAC and CP. Design Genome-wide variations of DNA-methylation, messenger RNA and microRNA level as well as combinations thereof were analysed in 345 tissue samples for marker identification. To improve diagnostic performance, we established a random-forest machine-learning approach. Results were validated on another 48 samples and further corroborated in 16 liquid biopsy samples. Results Machine-learning succeeded in defining markers to differentiate between patients with PDAC and CP, while low-dimensional embedding and cluster analysis failed to do so. DNA-methylation yielded the best diagnostic accuracy by far, dwarfing the importance of transcript levels. Identified changes were confirmed with data taken from public repositories and validated in independent sample sets. A signature of six DNA-methylation sites in a CpG-island of the protein kinase C beta type gene achieved a validated diagnostic accuracy of 100% in tissue and in circulating free DNA isolated from patient plasma. Conclusion The success of machine-learning to identify an effective marker signature documents the power of this approach. The high diagnostic accuracy of discriminating PDAC from CP could have tremendous consequences for treatment success, once the result from still a limited number of liquid biopsy samples would be confirmed in a larger cohort of patients with suspected pancreatic cancer.
Human GLP1R variants affecting GLP1R cell surface expression are associated with impaired glucose control and increased adiposity
Authors: Wenwen Gao, Lei Liu, Eunna Huh, Florence Gbahou, Erika Cecon, Masaya Oshima, Ludivine Houzé, Panagiotis Katsonis, Alan Hegron, Zhiran Fan, Guofei Hou, Guillaume Charpentier, Mathilde Boissel, Mehdi Derhourhi, Michel Marre, Beverley Balkau, Philippe Froguel, Raphael Scharfmann, Olivier Lichtarge, Julie Dam, Amélie Bonnefond, Jianfeng Liu, Ralf Jockers
Journal: Nature Metabolism (2023)
MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial
Authors: Jennifer M. Mitchell, Marcela Ot’alora G., Bessel van der Kolk, Scott Shannon, Michael Bogenschutz, Yevgeniy Gelfand, Casey Paleos, Christopher R. Nicholas, Sylvestre Quevedo, Brooke Balliett, Scott Hamilton, Michael Mithoefer, Sarah Kleiman, Kelly Parker-Guilbert, Keren Tzarfaty, Charlotte Harrison, Alberdina de Boer, Rick Doblin, Berra Yazar-Klosinski, Charlotte Harrison, Berra Yazar-Klosinski, Wael Garas, Darrick May, Cole Marta, Susan Walker, Elizabeth Nielson, Gregory Wells, Randall Brown, Revital Amiaz, Yair Wallach, Ray Worthy, Alia Lilienstein, Amy Emerson
Journal: Nature Medicine (2023)

This multi-site, randomized, double-blind, confirmatory phase 3 study evaluated the efficacy and safety of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) versus placebo with identical therapy in participants with moderate to severe post-traumatic stress disorder (PTSD). Changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score (primary endpoint) and Sheehan Disability Scale (SDS) functional impairment score (key secondary endpoint) were assessed by blinded independent assessors. Participants were randomized to MDMA-AT (n = 53) or placebo with therapy (n = 51). Overall, 26.9% (28/104) of participants had moderate PTSD, and 73.1% (76/104) of participants had severe PTSD. Participants were ethnoracially diverse: 28 of 104 (26.9%) identified as Hispanic/Latino, and 35 of 104 (33.7%) identified as other than White. Least squares (LS) mean change in CAPS-5 score (95% confidence interval (CI)) was -23.7 (-26.94, -20.44) for MDMA-AT versus -14.8 (-18.28, -11.28) for placebo with therapy (P < 0.001, d = 0.7). LS mean change in SDS score (95% CI) was -3.3 (-4.03, -2.60) for MDMA-AT versus -2.1 (-2.89, -1.33) for placebo with therapy (P = 0.03, d = 0.4). Seven participants had a severe treatment emergent adverse event (TEAE) (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 2 (3.9%)). There were no deaths or serious TEAEs. These data suggest that MDMA-AT reduced PTSD symptoms and functional impairment in a diverse population with moderate to severe PTSD and was generally well tolerated. ClinicalTrials.gov identifier: NCT04077437 .
Activation of the transcription factor NFAT5 in the tumor microenvironment enforces CD8+ T cell exhaustion
Authors: Laure Tillé, Daniela Cropp, Mélanie Charmoy, Patrick Reichenbach, Massimo Andreatta, Tania Wyss, Gabrielle Bodley, Isaac Crespo, Sina Nassiri, Joao Lourenco, Marine M. Leblond, Cristina Lopez-Rodriguez, Daniel E. Speiser, George Coukos, Melita Irving, Santiago J. Carmona, Werner Held, Grégory Verdeil
Journal: Nature Immunology (2023)
Optimized glycemic control of type 2 diabetes with reinforcement learning: a proof-of-concept trial
Authors: Guangyu Wang, Xiaohong Liu, Zhen Ying, Guoxing Yang, Zhiwei Chen, Zhiwen Liu, Min Zhang, Hongmei Yan, Yuxing Lu, Yuanxu Gao, Kanmin Xue, Xiaoying Li, Ying Chen
Journal: Nature Medicine (2023)

Abstract The personalized titration and optimization of insulin regimens for treatment of type 2 diabetes (T2D) are resource-demanding healthcare tasks. Here we propose a model-based reinforcement learning (RL) framework (called RL-DITR), which learns the optimal insulin regimen by analyzing glycemic state rewards through patient model interactions. When evaluated during the development phase for managing hospitalized patients with T2D, RL-DITR achieved superior insulin titration optimization (mean absolute error (MAE) of 1.10 ± 0.03 U) compared to other deep learning models and standard clinical methods. We performed a stepwise clinical validation of the artificial intelligence system from simulation to deployment, demonstrating better performance in glycemic control in inpatients compared to junior and intermediate-level physicians through quantitative (MAE of 1.18 ± 0.09 U) and qualitative metrics from a blinded review. Additionally, we conducted a single-arm, patient-blinded, proof-of-concept feasibility trial in 16 patients with T2D. The primary outcome was difference in mean daily capillary blood glucose during the trial, which decreased from 11.1 (±3.6) to 8.6 (±2.4) mmol L −1 ( P &lt; 0.01), meeting the pre-specified endpoint. No episodes of severe hypoglycemia or hyperglycemia with ketosis occurred. These preliminary results warrant further investigation in larger, more diverse clinical studies. ClinicalTrials.gov registration: NCT05409391 .
Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity
Authors: Peter M. K. Westcott, Francesc Muyas, Haley Hauck, Olivia C. Smith, Nathan J. Sacks, Zackery A. Ely, Alex M. Jaeger, William M. Rideout, Daniel Zhang, Arjun Bhutkar, Mary C. Beytagh, David A. Canner, Grissel C. Jaramillo, Roderick T. Bronson, Santiago Naranjo, Abbey Jin, J. J. Patten, Amanda M. Cruz, Sean-Luc Shanahan, Isidro Cortes-Ciriano, Tyler Jacks
Journal: Nature Genetics (2023)

DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy. Nevertheless, most MMRd tumors do not durably respond to ICB and critical questions remain about immunosurveillance and TMB in these tumors. In the present study, we developed autochthonous mouse models of MMRd lung and colon cancer. Surprisingly, these models did not display increased T cell infiltration or ICB response, which we showed to be the result of substantial intratumor heterogeneity of mutations. Furthermore, we found that immunosurveillance shapes the clonal architecture but not the overall burden of neoantigens, and T cell responses against subclonal neoantigens are blunted. Finally, we showed that clonal, but not subclonal, neoantigen burden predicts ICB response in clinical trials of MMRd gastric and colorectal cancer. These results provide important context for understanding immune evasion in cancers with a high TMB and have major implications for therapies aimed at increasing TMB.
Warming up cool cooperators
Authors: Eamonn Ferguson, Claire Lawrence, Sarah Bowen, Carley N. Gemelli, Amy Rozsa, Konrad Niekrasz, Anne van Dongen, Lisa A. Williams, Amanda Thijsen, Nicola Guerin, Barbara Masser, Tanya E. Davison
Journal: Nature Human Behaviour (2023)

Abstract Explaining why someone repeats high-cost cooperation towards non-reciprocating strangers is difficult. Warm glow offers an explanation. We argue that warm glow, as a mechanism to sustain long-term cooperation, cools off over time but can be warmed up with a simple intervention message. We tested our predictions in the context of repeat voluntary blood donation (high-cost helping of a non-reciprocating stranger) across 6 studies: a field-based experiment ( n = 5,821) comparing warm-glow and impure-altruism messages; an implementation study comparing a 3-yr pre-implementation period among all first-time donors in Australia ( N = 270,353) with a 2-yr post-implementation period ( N = 170, 317); and 4 studies ( n = 716, 1,124, 932, 1,592) exploring mechanisms. We show that there are relatively warm and cool cooperators, not cooling cooperators. Cooperation among cool cooperators is enhanced by a warm-glow-plus-identity message. Furthermore, the behavioural facilitation of future cooperation, by booking an appointment, is associated with being a warm cooperator. Societal implications are discussed.
Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease
Authors: Yanhua Chen, Xiaomeng Du, Annapurna Kuppa, Mary F. Feitosa, Lawrence F. Bielak, Jeffrey R. O’Connell, Solomon K. Musani, Xiuqing Guo, Bratati Kahali, Vincent L. Chen, Albert V. Smith, Kathleen A. Ryan, Gudny Eirksdottir, Matthew A. Allison, Donald W. Bowden, Matthew J. Budoff, John Jeffrey Carr, Yii-Der I. Chen, Kent D. Taylor, Antonino Oliveri, Adolfo Correa, Breland F. Crudup, Sharon L. R. Kardia, Thomas H. Mosley, Jill M. Norris, James G. Terry, Jerome I. Rotter, Lynne E. Wagenknecht, Brian D. Halligan, Kendra A. Young, John E. Hokanson, George R. Washko, Vilmundur Gudnason, Michael A. Province, Patricia A. Peyser, Nicholette D. Palmer, Elizabeth K. Speliotes
Journal: Nature Genetics (2023)
Axicabtagene ciloleucel as second-line therapy in large B cell lymphoma ineligible for autologous stem cell transplantation: a phase 2 trial
Authors: Roch Houot, Emmanuel Bachy, Guillaume Cartron, François-Xavier Gros, Franck Morschhauser, Lucie Oberic, Thomas Gastinne, Pierre Feugier, Rémy Duléry, Catherine Thieblemont, Magalie Joris, Fabrice Jardin, Sylvain Choquet, Olivier Casasnovas, Gabriel Brisou, Morgane Cheminant, Jacques-Olivier Bay, Francisco Llamas Gutierrez, Cédric Menard, Karin Tarte, Marie-Hélène Delfau, Cédric Portugues, Emmanuel Itti, Xavier Palard-Novello, Paul Blanc-Durand, Yassine Al Tabaa, Clément Bailly, Camille Laurent, François Lemonnier
Journal: Nature Medicine (2023)

Abstract Axicabtagene ciloleucel (axi-cel) demonstrated superior efficacy compared to standard of care as second-line therapy in patients with high-risk relapsed/refractory (R/R) large B cell lymphoma (LBCL) considered eligible for autologous stem cell transplantation (ASCT); however, in clinical practice, roughly half of patients with R/R LBCL are deemed unsuitable candidates for ASCT. The efficacy of axi-cel remains to be ascertained in transplant-ineligible patients. ALYCANTE, an open-label, phase 2 study, evaluated axi-cel as a second-line therapy in 62 patients with R/R LBCL who were considered ineligible for ASCT. The primary end point was investigator-assessed complete metabolic response at 3 months from the axi-cel infusion. Key secondary end points included progression-free survival, overall survival and safety. The study met its primary end point with a complete metabolic response of 71.0% (95% confidence interval, 58.1–81.8%) at 3 months. With a median follow-up of 12.0 months (range, 2.1–17.9), median progression-free survival was 11.8 months (95% confidence interval, 8.4–not reached) and overall survival was not reached. There was no unexpected toxicity. Grade 3–4 cytokine release syndrome and neurologic events occurred in 8.1% and 14.5% of patients, respectively. These results support axi-cel as second-line therapy in patients with R/R LBCL ineligible for ASCT. ClinicalTrials.gov Identifier: NCT04531046 .
Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial
Authors: Byoung Chul Cho, Dong-Wan Kim, Alexander I. Spira, Jorge E. Gomez, Eric B. Haura, Sang-We Kim, Rachel E. Sanborn, Eun Kyung Cho, Ki Hyeong Lee, Anna Minchom, Jong-Seok Lee, Ji-Youn Han, Misako Nagasaka, Joshua K. Sabari, Sai-Hong Ignatius Ou, Patricia Lorenzini, Joshua M. Bauml, Joshua C. Curtin, Amy Roshak, Grace Gao, John Xie, Meena Thayu, Roland E. Knoblauch, Keunchil Park
Journal: Nature Medicine (2023)

Abstract Patients with epidermal growth factor receptor ( EGFR )-mutated non-small cell lung cancer (NSCLC) often develop resistance to current standard third-generation EGFR tyrosine kinase inhibitors (TKIs); no targeted treatments are approved in the osimertinib-relapsed setting. In this open-label, dose-escalation and dose-expansion phase 1 trial, the potential for improved anti-tumor activity by combining amivantamab, an EGFR-MET bispecific antibody, with lazertinib, a third-generation EGFR TKI, was evaluated in patients with EGFR -mutant NSCLC whose disease progressed on third-generation TKI monotherapy but were chemotherapy naive (CHRYSALIS cohort E). In the dose-escalation phase, the recommended phase 2 combination dose was established; in the dose-expansion phase, the primary endpoints were safety and overall response rate, and key secondary endpoints included progression-free survival and overall survival. The safety profile of amivantamab and lazertinib was generally consistent with previous experience of each agent alone, with 4% experiencing grade ≥3 events; no new safety signals were identified. In an exploratory cohort of 45 patients who were enrolled without biomarker selection, the primary endpoint of investigator-assessed overall response rate was 36% (95% confidence interval, 22–51). The median duration of response was 9.6 months, and the median progression-free survival was 4.9 months. Next-generation sequencing and immunohistochemistry analyses identified high EGFR and/or MET expression as potential predictive biomarkers of response, which will need to be validated with prospective assessment. ClinicalTrials.gov identifier: NCT02609776 .
Somatic SLC30A1 mutations altering zinc transporter ZnT1 cause aldosterone-producing adenomas and primary aldosteronism
Authors: Juilee Rege, Sascha Bandulik, Kazutaka Nanba, Carla Kosmann, Amy R. Blinder, Allein Plain, Pankaj Vats, Chandan Kumar-Sinha, Antonio M. Lerario, Tobias Else, Yuto Yamazaki, Fumitoshi Satoh, Hironobu Sasano, Thomas J. Giordano, Tracy Ann Williams, Martin Reincke, Adina F. Turcu, Aaron M. Udager, Richard Warth, William E. Rainey
Journal: Nature Genetics (2023)
Amyloid fibril proteomics of AD brains reveals modifiers of aggregation and toxicity
Authors: Arun Upadhyay, Deepak Chhangani, Nalini R. Rao, Julia Kofler, Robert Vassar, Diego E. Rincon-Limas, Jeffrey N. Savas
Journal: Molecular Neurodegeneration (2023)

The accumulation of amyloid beta (Aβ) peptides in fibrils is prerequisite for Alzheimer's disease (AD). Our understanding of the proteins that promote Aβ fibril formation and mediate neurotoxicity has been limited due to technical challenges in isolating pure amyloid fibrils from brain extracts.
A genome-wide in vivo CRISPR screen identifies essential regulators of T cell migration to the CNS in a multiple sclerosis model
Authors: Arek Kendirli, Clara de la Rosa, Katrin F. Lämmle, Klara Eglseer, Isabel J. Bauer, Vladyslav Kavaka, Stephan Winklmeier, La Zhuo, Christian Wichmann, Lisa Ann Gerdes, Tania Kümpfel, Klaus Dornmair, Eduardo Beltrán, Martin Kerschensteiner, Naoto Kawakami
Journal: Nature Neuroscience (2023)

Abstract Multiple sclerosis (MS) involves the infiltration of autoreactive T cells into the CNS, yet we lack a comprehensive understanding of the signaling pathways that regulate this process. Here, we conducted a genome-wide in vivo CRISPR screen in a rat MS model and identified 5 essential brakes and 18 essential facilitators of T cell migration to the CNS. While the transcription factor ETS1 limits entry to the CNS by controlling T cell responsiveness, three functional modules, centered around the adhesion molecule α4-integrin, the chemokine receptor CXCR3 and the GRK2 kinase, are required for CNS migration of autoreactive CD4 + T cells. Single-cell analysis of T cells from individuals with MS confirmed that the expression of these essential regulators correlates with the propensity of CD4 + T cells to reach the CNS. Our data thus reveal key regulators of the fundamental step in the induction of MS lesions.
CAP2 promotes gastric cancer metastasis by mediating the interaction between tumor cells and tumor-associated macrophages
Authors: Guohao Zhang, Zhaoxin Gao, Xiangyu Guo, Ranran Ma, Xiaojie Wang, Pan Zhou, Chunlan Li, Zhiyuan Tang, Ruinan Zhao, Peng Gao
Journal: Journal of Clinical Investigation (2023)

The metastasis of cancer cells is the main cause of death in patients with gastric cancer (GC). Mounting evidence has demonstrated the vital importance of tumor-associated macrophages in promoting tumor invasion and metastasis; however, the interaction between tumor cells and macrophages in GC is largely unknown. In this study, we demonstrated that cyclase-associated protein 2 (CAP2) was upregulated in GC, especially in cases with lymph node metastasis, and was correlated with a poorer prognosis. The transcription factor JUN directly bound to the promoter region of CAP2 and activated CAP2 transcription. The N-terminal domain of CAP2 bound to the WD5 to WD7 domains of receptor for activated C kinase 1 (RACK1) and induced M2 macrophage polarization by activating the SRC/focal adhesion kinase (FAK)/ERK signaling pathway, which resulted in IL-4 and IL-10 secretion. Polarized M2 macrophages induced premetastatic niche formation and promoted GC metastasis by secreting TGFB1, which created a TGFB1/JUN/CAP2 positive-feedback loop to activate CAP2 expression continuously. Furthermore, we identified salvianolic acid B as an inhibitor of CAP2, which effectively inhibited GC cell invasion capabilities by suppressing the SRC/FAK/ERK signaling pathway. Our data suggest that CAP2, a key molecule mediating the interaction between GC cells and tumor-associated macrophages, may be a promising therapeutic target for suppressing tumor metastasis in GC.
Provision of evaluation and management visits by nurse practitioners and physician assistants in the USA from 2013 to 2019: cross-sectional time series study
Authors: Sadiq Y Patel, David Auerbach, Haiden A Huskamp, Austin Frakt, Hannah Neprash, Michael L Barnett, Hannah O James, Laura Barrie Smith, Ateev Mehrotra
Journal: BMJ (2023)

Abstract Objective To examine the proportion of healthcare visits are delivered by nurse practitioners and physician assistants versus physicians and how this has changed over time and by clinical setting, diagnosis, and patient demographics. Design Cross-sectional time series study. Setting National data from the traditional Medicare insurance program in the USA. Participants Of people using Medicare (ie, those older than 65 years, permanently disabled, and people with end stage renal disease), a 20% random sample was taken. Main outcome measures The proportion of physician, nurse practitioner, and physician assistant visits in the outpatient and skilled nursing facility settings delivered by physicians, nurse practitioners, and physician assistants, and how this proportion varies by type of visit and diagnosis. Results From 1 January 2013 to 31 December 2019, 276 million visits were included in the sample. The proportion of all visits delivered by nurse practitioners and physician assistants in a year increased from 14.0% (95% confidence interval 14.0% to 14.0%) to 25.6% (25.6% to 25.6%). In 2019, the proportion of visits delivered by a nurse practitioner or physician assistant varied across conditions, ranging from 13.2% for eye disorders and 20.4% for hypertension to 36.7% for anxiety disorders and 41.5% for respiratory infections. Among all patients with at least one visit in 2019, 41.9% had one or more nurse practitioner or physician assistant visits. Compared with patients who had no visits from a nurse practitioner or physician assistant, the likelihood of receiving any care was greatest among patients who were lower income (2.9% greater), rural residents (19.7%), and disabled (5.6%). Conclusion The proportion of visits delivered by nurse practitioners and physician assistants in the USA is increasing rapidly and now accounts for a quarter of all healthcare visits.
Author Correction: The gut microbial metabolite formate exacerbates colorectal cancer progression
Authors: Dominik Ternes, Mina Tsenkova, Vitaly Igorevich Pozdeev, Marianne Meyers, Eric Koncina, Sura Atatri, Martine Schmitz, Jessica Karta, Maryse Schmoetten, Almut Heinken, Fabien Rodriguez, Catherine Delbrouck, Anthoula Gaigneaux, Aurelien Ginolhac, Tam Thuy Dan Nguyen, Lea Grandmougin, Audrey Frachet-Bour, Camille Martin-Gallausiaux, Maria Pacheco, Lorie Neuberger-Castillo, Paulo Miranda, Nikolaus Zuegel, Jean-Yves Ferrand, Manon Gantenbein, Thomas Sauter, Daniel Joseph Slade, Ines Thiele, Johannes Meiser, Serge Haan, Paul Wilmes, Elisabeth Letellier
Journal: Nature Metabolism (2023)

In the